Pharmaceutical compositions

ABSTRACT

Pharmaceutical compositions for oral administration, in particular administration as an oral delivery system to be swallowed directly or capable of disintegration in the oral cavity, comprising iron oxy-hydroxide in high loading.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions comprising ironoxy-hydroxide in high loading in a form suitable for oraladministration, and in particular for administration as an oral deliverysystem either as dosage forms for intact swallowing (e.g. film-coated)or as dosage forms capable of rapid disintegration, as well as methodsof production thereof.

BACKGROUND

In patients with chronic renal insufficiency, a pathologically increasedserum phosphate level occurs due to the decrease in the glomerularfiltration rate. The secondary hyperparathyroidism which sets intherewith must be considered as one of the causes of the occurrence ofrenal osteopathy. Attempts are normally made to maintain the phosphatebalance in equilibrium by dialysis or by the administration of oralphosphate adsorbers which suppress the resorption of foodstuffphosphates in the gastrointestinal tract, or by the combination of bothmethods, but with the current state of the art this is either notefficient enough, is not economic, or is burdened with side effects.

Recently new and effective phosphate adsorbers based on ironoxy-hydroxide, in particular containing beta-iron oxy-hydroxidestabilised by a stabilization agent such as a carbohydrate and/or humicacid, have been described (EP 0 368 125). These adsorbents show superiorphosphate adsorption capacity from aqueous solutions, for example forthe adsorption of inorganic phosphates and phosphates bonded tofoodstuffs (EP 0 868 125) and have been shown to be efficient oralphosphate binders in the treatment of hyperphosphataemia (Neophrol.Dial. Transplant 14, 863: 1999).

To achieve maximum efficiency while maintaining good patient compliance,it is desirable that such adsorbers can be administered in high dosages.However, phosphate adsorbers with high iron loadings are still notavailable. Factors, such as ease of administration in general,unacceptable taste, as well as storage and stability problems, limit theapplicability of currently available phosphate binders.

WO 2006/000547 of the present applicant discloses a process forpreparing an iron-sulfate based phosphate adsorbent, which may be usedfor preventing and treating hyperphosphatemic conditions. Described areiron oxy hydroxide compositions which are prepared form ferric sulphateand/or nitrate containing a stabilising agent selected from humic acidand carbohydrates and which have an iron content of at most 20.3 to22.3% by weight. These compositions are obtained by rotary evaporation.No specific oral formulations such as tablets are disclosed, it isexplained that the iron compositions can be formulated to tablets orother oral formulations together with usual excipients and adjuvants.This means that tablets obtained from the iron oxy hydroxidecompositions can have an iron content of at most 20% (w/w) correspondingto 32% (w/w) iron oxy-hydroxide.

EP 1 757 299 of the present applicant describes iron(III) carbohydratecomplex compounds and there use for orally or parenterally treating irondeficiency in patients having chronic inflammatory bowel disease In thedocument reference is made to Maltofer® film tablets containing 100 mgiron(III). The iron content of the tablet is 16% by weight correspondingto 25.6% w/w iron oxy-hydroxide. The preparation is intended fortreating iron deficiency, that is, for liberating iron(III), contrary tophosphate adsorbents as defined in the present invention. No dryingprocedure is described.

WO 92/01458 discloses oxy-iron compounds, in particular iron oxides ironhydroxides and iron oxy hydroxides which are formulated as a therapeuticdosage form for use as a phosphate adsorber. No specific oralformulations are disclosed, and no specific iron loading is mentioned.Further, no excipients and manufacturing methods are specificallydisclosed, but reference is made to “acceptable methods and excipients”.It is said that each oral dose may contain 50 mg to about 500 mg or moreof oxy-iron compound. According to the state of the art tabletscontaining 500 mg oxy-iron compounds, which are necessary in order toachieve a desired degree of phosphate adsorption, would be of such anenormous size that they could not be swallowed by the patient. Thedocument does not disclose anything as to obtaining a high iron loading.

U.S. Pat. No. 5,514,281 discloses polynuclear iron oxy hydroxides boundto a support such as saponified divinylethylene urea vinylacetatecopolymer, Lewatit R®, silica, glasses and organic porous supportsmodified with dextran. The maximum iron loading of a support carryingiron(III) is reported to be 29.3% by dry weight The product is formedfrom a dry support, which is swelled, and it may not be dried thereaftersince otherwise removal of phosphate from the dialysate would not workat all. None of the examples in U.S. Pat. No. 5,514,281 describes adry/tablet formulation for oral administration. The examples givendescribing adsorbents are all meant for extracorporal use and none ofthe supports used for their production is applicable for medicinal use.The preparation of an oral formulation is only described as “pressedinto powder for . . . ”. These products are developed to release iron.

For a wide range of drugs, oral dosage forms such as tablets are clearlythe preferred form of delivery. This is due to a high level of patientacceptability and compliance (because they provide an accurate dosageand are easy to administer) as well as advantageous characteristicsduring and after manufacture, such as they typically show satisfactoryphysical and chemical stability, are convenient for packing, shippingand administering and offer advantages in manufacturing speed and cost.

However, oral dosage forms need carefully designed disintegrationcharacteristics to achieve the desired bioavailability for theincorporated drug, i.e. dissolution must precede absorption, in case ofimmediate release tablets should disintegrate rapidly after ingestion inorder to facilitate dissolution of the drug. Moreover, the drug loadingof conventional tablet formulations is often limited due to potentialgastrointestinal irritation (caused by locally high concentration)and/or patient compliance (which limits size and shape to achieve easyswallowing).

These limitations have prevented the development of an effective oraldelivery system for iron oxy-hydroxide as phosphate binder with highloadings.

Applicants have now found that iron oxy-hydroxide (hereinafter alsoreferred to as active agent), and in particular iron oxy-hydroxidecontaining beta-iron oxy-hydroxide, and in particular further containinga carbohydrate and/or humic acid that may act as a stabilization agentas described in EP 0 868 125 B1, can be successfully formulated in formof an oral delivery system with high loadings (hereinafter also calledpharmaceutical compositions or compositions of the invention),preferably either as dosage forms for intact swallowing (e. g.film-coated) or as dosage forms capable of rapid disintegration (eitherin the oral cavity or in a small amount of liquid prior to ingestion).Thus the pharmaceutical compositions of the invention are able toachieve both high loadings and suitable disintegration characteristicswhile maintaining a minimal size and thus are able to overcome thedrawbacks of currently known formulations.

The inventive compositions have a low iron release rate of below 2.5%w/w, which is essential for phosphate adsorbers. In contrast thereto.compositions used for treating iron deficiency have a high iron releaserate and thus are completely different form the inventive compositions.

Furthermore it was found that the pharmaceutical compositions of theinvention can be preferably obtained through conventional molding ortableting methods, more preferably direct compression tableting methods,in the presence of one or more excipients fulfilling for example thefunctions of binder and/or filler and/or disintegrant in one.

It was further found that any disagreeable taste associated with theactive agent, if administered as dosage forms capable of disintegrationin the oral cavity, can be eliminated using suitable taste-maskingagents, sweeteners and/or taste-enhancing agents.

Further it was found that favourable tablet formulations with aparticularly high iron-oxy-hydroxide-load can be obtained, if they arecomprised of substantial amounts of a flowable powder that has beenprepared by spray-drying an aqueous suspension of the ingredients.

SUMMARY OF THE INVENTION

It is an object of the invention to provide pharmaceutical compositionscomprising iron oxy-hydroxide in a form suitable for oraladministration, in particular as an oral delivery system with highloadings, preferably either as dosage forms for intact swallowing (e.g.film-coated) or as dosage forms capable of rapid disintegration (eitherin the oral cavity or in a small amount of liquid prior to ingestion).

In a preferred embodiment the iron oxy-hydroxide-containingpharmaceutical composition comprises one or more carbohydrates and/orhumic acid, preferably a carbohydrate such as a mono- di- orpolysaccharide, preferably saccharose (sucrose), starch, agarose,dextran, dextrin, cellulose and derivatives of each of these. Thosecarbohydrates and/or humic acid may act as a stabilization agent asdescribed in EP 0 868 125 B1. Apart from this or in addition to this thecarbohydrate(s) and/or humic acid may act as a binder and/or fillerand/or disintegrant.

In yet another embodiment the compositions of the invention comprise oneor more taste-masking and/or coloring additives such as flavouringagents, sweeteners, taste-enhancing agents, colorants, and the like.Depending on the intended use of the tablet, i.e. whether it is forintact swallowing or rapid disintegration (in the oral cavity or in asmall amount of liquid prior to ingestion), such as e.g. a chewabletablet, usual excipients, such as superdisintegrants, glidants,lubricants, antioxidants compression aids and the like may be added ifdesired. The tablet may be coated with usual film-forming agents, ifdesired.

In another embodiment, the pharmaceutical compositions of the inventionare in any dosage form suitable for oral administration and inparticular include tablets and pills, either in a form for intactswallowing (e.g. film-coated) or in a form capable of rapiddisintegration (either in the oral cavity after ingestion or in a smallamount of liquid prior to ingestion), including a chewable form, drypowders. granules, capsules or sachets containing these, granules,wafers, films, lozenges, and the like.

It is a further object of the invention to provide methods forformulating an oral delivery system according to the invention, inparticular an oral delivery system either as dosage forms for intactswallowing (e.g. film-coated) or as dosage forms capable of rapiddisintegration (either in the oral cavity or in a small amount of liquidprior to ingestion), comprising iron oxy-hydroxide in high loadings, bymeans of conventional molding or tableting methods, preferably directcompression tableting methods.

DETAILED DESCRIPTION OF THE INVENTION

Thus, in a first aspect the present invention is directed topharmaceutical compositions comprising iron oxy-hydroxide as an activeagent in high loadings and in a form suitable for oral administrationshowing the desired disintegration characteristics.

In particular, the present invention is directed to such orallyadministrable, pharmaceutical compositions with high loadings of theactive agent, either as dosage forms for intact swallowing (e.g.film-coated) or as dosage forms capable of rapid disintegration (eitherin the oral cavity or in a small amount of liquid prior to ingestion).

As indicated hereinabove, the term “active agent” as used hereinincludes iron(III)-oxy-hydroxide. Iron(III)-oxy-hydroxide oriron(III)-oxide-hydroxide is usually referred to as FeO(OH) orFe₂O₃xH₂O. Such iron oxy-hydroxides to be used in accordance with thepresent invention are usually formed upon hydrolysis and precipitationin aqueous iron(III)-salt solutions (see, for example, Römpp LexikonChemie, 10. Auflage, 1997; U. Schwertmann. R. M. Cornell “Iron Oxides inthe Laboratory”, VCH Veriagsgesellschaft mbH, 1991, Seiten 95-100). Theterm “iron oxy-hydroxide” as used herein thus includes, in particular,alpha, beta, gamma, and delta FeOOH and mixtures thereof. Preferably,the iron oxy-hydroxide comprises beta FeOOH optionally in admixture withother iron oxy-hydroxide(s).

Iron oxy-hydroxides to be used in accordance with the present inventionare preferably prepared by adding a base to an aqueous iron(III)-saltsolution as described in EP 0868125 B1, and subsequent drying.

Preferably iron oxy-hydroxide stabilized by a stabilization agent isused.

The wording “iron oxy-hydroxide. which is stabilized by a stabilizationagent” includes preferably an iron oxy-hydroxide together with astabilization agent, which includes in particular carbohydrates andhumic acid. As described in EP 0868125 B1 such stabilization agentusually is not bound as a complex compound to the iron oxy-hydroxide,which means for example that a water-soluble stabilization agent can beremoved by washing the stabilized iron oxy-hydroxide with water. Asfurther described in EP 0868125 B1 the stabilization agent is supposedto stabilize the iron oxy-hydroxide against ageing, thereby preservingits phosphate adsorption capacity. This means that a stabilized ironoxy-hydroxide in general has a higher phosphate adsorption capacity (asmeasured in EP 0868125 B1) compared to a non-stabilized ironoxy-hydroxide. In a accordance with the present invention a preferred“iron oxy-hydroxide, which is stabilized by a stabilization agent”comprises beta iron oxy-hydroxide stabilized as described in EP 0868125B1 with at least one carbohydrate and/or humic acid.

Generally, due to their chemical nature the iron oxy-hydroxides used andadministered in accordance with the present invention essentially arenot absorbed by the human body, i.e. they are essentiallynon-bioabsorbable.

Accordingly the term “stabilization agent” as used herein includespreferably at least one carbohydrate and/or humic acid, in particular,as described in EP 0868125 B1. In one embodiment, the at least onecarbohydrate is soluble and includes at least one mono-, di- orpolysaccharide, such as agarose, dextran, dextrin, dextran derivatives,cellulose and cellulose derivatives, saccharose (sucrose), maltose orlactose preferably saccharose (sucrose), dextrin or starch.

The term “starch” as used herein includes any conventionally used starchproducts (such as potato starch, corn starch, rice starch, tapiocastarch) in native, pregelatinized, degraded, modified, and derivatizedforms, preferably suitable for direct compression, and mixtures thereof.

Preferred products include native and pregelatinized starch, such as ina mixture having a ratio (native.pregelatinized) in the range of 10:1 to0.5:1, preferably in the range of 3:1 to 0.5:1 more preferably in therange of 2:1 to 1:1. The use of a mixture of native and pregelatinizedstarch has turned out be particularly advantageous in the manufacture ofa tablet with high iron loading, since it allows the preparation of astabilized pre-mixture which can be compressed to a suitable tableteither directly or with a very small amount of further excipients.

In one specific embodiment the stabilization agent of choice may bepresent in an amount of 1.0 to 50% (w/w), preferably 5.0 to 30% (w/w).

All % weights (w/w) throughout this description are expressed inrelation to the total weight of the pharmaceutical composition, if notindicated otherwise.

The term “high loading” as used herein indicates that the ironoxy-hydroxide is present in an amount of 10 to 30% (w/w) more preferably30 to 65% (w/w).

The content of iron oxy-hydroxide is calculated as approximately 1.6×content of iron.

Thus, the values mentioned above correspond to a content of iron of 6 to50% w/w, more preferably 19 to 41% (w/w).

In preferred embodiments of the invention even higher iron loadings arerealized, namely more than 50% (w/w) to 90% (w/w) iron oxy-hydroxide,preferably 56%-65% (w/w) corresponding to 31 to 56% (w/w), preferably35% to 41% (w/w) iron.

Or else, the iron oxy-hydroxide is preferably present in an amountof >300 mg per dosage form, more preferably 300 to 2000 mg per dosageform. It is understood that the amount of active agent depends on theintended administration route, i.e. the amount present in tablets forintact swallowing film coated e.g. film-coated) are preferably 350 to850 mg whereas the amount present in oral dosage forms capable of rapiddisintegration (either in the oral cavity or in a small amount of liquidprior to ingestion) are preferably 700 to 1700 mg.

In addition to the active agent, conventional pharmaceuticalcompositions typically contain a number of additional inactiveingredients known as excipients and/or additives. In particular when theamount of active agent required to accomplish a desired therapeutic,nutritive or chemical effect is very small, the presence of inertdiluents, fillers, binders, excipients and disintegrants, lubricants,glidants, and sweeteners, taste masking agents, colorants, and the likeusually is critical to ensure the practicality and convenience of makingoral dosage forms to achieve accurate and effective administration ofthe active agent.

In contrast, in case of orally administered pharmaceutical compositionshaving high loadings of active agent, as in the present invention, suchadditional inactive ingredients are minimized, since the size of anorally administered pharmaceutical composition is a critical feature forachieving good patient compliance.

As explained above, a carbohydrate such as a mono- di- orpolysaccharide, preferably saccharose (sucrose), starch, agarose,dextran, dextrin, cellulose and derivatives of each of these, morepreferably saccharose (sucrose), dextrin or starch may, apart from or inaddition to its stabilizing effect on the iron-oxy hydroxide, act as abinder and/or filter and/or disintegrant in the pharmaceuticalcomposition of the present invention.

Thus, a preferred composition of the invention may comprise ironoxy-hydroxide in the amounts specified above, a stabilization agent ofchoice in an amount of 1.0 to 50% (w/w), preferably 5.0 to 30% (w/w),and an excipient of choice, different from the stabilizing agent, in anamount of 1.0 to 50% (w/w), preferably 5.0 to 30% (w/w), each expressedin relation to the total weight of the composition.

In another embodiment the compositions of the invention comprise one ormore taste-masking and coloring additives such as flavouring agents,sweeteners, taste-enhancing agents, colorants, and the like, which aretypically used for oral dosage forms.

Taste-masking agents, such as a taste-enhancing agent, flavouring agent,and/or natural or unnatural sweetener, including intense sweetener, areincorporated into oral dosage forms, such as chewable dosage forms, togive them a more pleasant taste or to mask an unpleasant one.

Typical sweeteners include, but are not limited to, a sugar which isdextrose, sucrose, fructose, lactose confectionery sugar, powderedsugar, or is a polyol which is sorbitol (e.g. Neosorb), xylitol,maltitol, maltose and polydextrose, or a mixture thereof. Typicalintense sweeteners may include, but not be limited to, aspartame,sucralose, acesulfamine K, and/or saccharin derivatives, or a mixturethereof.

Further suitable sweeteners or taste-enhancing agents include glycosidessuch as neohesperidin dihydrochalcone (neohesperidin DC or NHDC),glycyrrhizin, glutamate, and the like. The latter may be used in verysmall quantities and thus may hereinafter also be called taste-enhancingagents. All the above are suitable to be used alone or as mixtures withother sweeteners and/or flavouring agents. These substances insure greatlingering of the sweet taste and cover any undesired aftertaste.Preferred sweeteners and/or taste-enhancing agents include glycosidessuch as neohesperidin dihydrochalcone.

In one embodiment the sweetener of choice may be present in an amount of0.01 to 2.5% (w/w), preferably 0.1 to 1.5% (w/w), most preferably 0.2 to1.0% (w/w), in relation to the total weight of the composition.

The taste-enhancing agent of choice may be present in an amount of 0.1to 50 ppm, preferably 1 to 10 ppm, most preferably 1 to 5 ppm, inrelation to the total weight of the composition.

Typical flavouring agents include any natural and unnatural flavouringagent suitable for pharmaceutical applications, such as flavouringagents derived from a spice, fruit or fruit juice, vegetable orvegetable juice, and the like, for example flavours based on cocoa,caramel, vanilla, apple, apricot, berry (e.g. blackberry, red currant,black currant, strawberry, raspberry, woodberry, etc.), mint, panettone,honey, nut, malt, cola, verveine (verbena) or any combination thereof,such as for example caramel/vanilla, fruit/cream (e.g.strawberry/cream)and the like.

In one embodiment the flavouring agent of choice may be present in anamount of 0.01 to 10% (w/w), preferably 0.1 to 5% (w/w), most preferably0.1 to 1% (w/w), in relation to the total weight of the composition.

Thus, another composition of the invention may comprise ironoxy-hydroxide in the amounts specified above, a stabilization agent ofchoice in an amount of 1.0 to 50% (w/w), preferably 5.0 to 30% (w/w), anexcipient of choice, different from the stabilization agent, in anamount of 1.0 to 50% (w/w). preferably 5.0 to 30% (w/w), andtaste-enhancing agent of choice, which may be present in an amount of0.1 to 50 ppm, preferably 1 to 10 ppm, most preferably 1 to 5 ppm,and/or a flavouring agent of choice, which may be present in an amountof 0.01 to 10% (w/w), preferably 0.1 to 5% (w/w), most preferably 0.1 to1% (w/w), each in relation to the total weight of the composition.

In yet another embodiment excipients, such as superdisintegrants,glidants, lubricants, antioxidants and the like may be added to thecompositions of the invention if desired, depending on the intended useof the tablet, i.e. whether it is for intact swallowing or rapiddisintegration (in the oral cavity or in a small amount of liquid priorto ingestion).

Thus in a particular embodiment the compositions of the invention mayfurther comprise a superdisintegrant.

The term “superdisintegrant” as used herein refers to a group ofdisintegration agents well-known to a person skilled in the art, whichcan be used in a fractional amount of normal disintegrants to obtain thesame effect of facilitating the disintegration or “breakup” of thedosage form after administration. Suitable examples include but are notlimited to cross-linked polyvinylpyrrolidones (commercially available asKollidon® CL and Polyplasdone® XL), particularly crospovidone®, modifiedstarches, particularly sodium starch glycolate (commercially availableunder the trade names Primojel® and Expiotab®), Starch 1500, modifiedcelluloses, particularly croscarmellose sodium (cross-linked sodiumcarboxymethylcellulose, commercially available under the trade nameAc-Di-Sol), LHPC (Low substituted hydroxypropylcellulose) and Veegum®.Preferred examples for use in the tablet according to the inventioninclude cross-linked polyvinylpyrrolidones and modified starches,particularly sodium starch glycolate.

According to the invention, the superdisintegrant will be present in thetablet in an amount of 0.1 to 10% (w/w), preferably 0.5 to 8% (w/w),more preferably 2.5 to 6% (w/w), in relation to the total weight of thecomposition. The superdisintegrant may be a single superdisintegrant ora combination of superdisintegrants or may be used in combination withone or more common disintegrants, such as for example starches,methylcellulose, calcium carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl cellulose, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium,pregelatinized starch, clays, cellulose, powdered cellulose,pregelatinized starch, sodium alginate, alginic acid, guar gum,magnesium aluminum silicate, polacrilin potassium, and the like.

Thus, another composition of the invention may comprise ironoxy-hydroxide in the amounts specified above, a stabilization agent ofchoice in an amount of 1.0 to 50% (w/w), preferably 5.0 to 30% (w/w), anexcipient of choice, different from the stabilization agent, in anamount of 1.0 to 50% (w/w), preferably 5.0 to 30% (w/w), said excipientcomprising a superdisintegrant in an amount of 0.1 to 10%, preferably0.5 to 8% (w/w), more preferably 2.5 to 6% (w/w), and a taste-enhancingagent of choice in an amount of 0.1 to 50 ppm (w/w), preferably 1 to 10ppm (w/w), more preferably 1 to 5 ppm (w/w), and/or a flavouring agentof choice in an amount of 0.01 to 10% (w/w), preferably 0.1 to 5% (w/w),more preferably 0.1 to 1% (w/w), all weight ranges are in relation tothe total weight of the composition.

In yet another embodiment the compositions of the invention may furthercomprise a glidant and/or lubricant.

The term “glidant” and/or “lubricant” as used herein refers to a groupof additives that are used to facilitate tablet manufacture by achievingsuitable flowability, compressability, and the like. Examples ofsuitable glidants include, but are not limited to, magnesium oxide,magnesium stearate, calcium stearate, stearic acid, glyceryl behenate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil type I, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, polyethylene glycol, talcum, zincstearate, silica derivatives, such as colloidal silica (e.g. Aerosil®)pyrogenic silica, hydrated sodium silicoaluminate, colloidal silicondioxide, and mineral oil and light mineral oil.

Preferred glidants include magnesium oxide, magnesium stearate, talcum,colloidal silica.

In one embodiment the glidant of choice may be present in an amount of0.01 to 10% (w/w), preferably 0.1 to 5% (w/w), most preferably 1 to 2%(w/w), in relation to the total weight of the composition.

Further additives specifically used for oral dosage forms capable ofrapid disintegration in the oral cavity, may include salivating agents(compounds that are able to stimulate production of saliva) to easeswallowing. These are in general pharmaceutically acceptable acids, forexample citric acid, malic acid, tartrate, or the compounds Optamint®and Optaflow®. Care has to be taken that iron release is not increasedby the use of such acidic compounds, e.g. citric acid, and the amount ofthese substances therefore has to chosen suitably. In one embodiment theacid of choice may be present in an amount of 0.01 to 10% (w/w),preferably 0.1 to 5% (w/w), most preferably 2 to 5% (w/w), in relationto the total weight of the composition.

As mentioned hereinabove, the pharmaceutical compositions are in a formsuitable for oral administration for the selective removal of inorganicphosphate, and in particular for administration as an oral deliverysystem either as film-coated dosage forms for intact swallowing or asdosage forms capable of disintegration (in the oral cavity or in a smallamount of liquid prior to ingestion).

Thus, the pharmaceutical composition of the invention include any dosageform suitable for oral administration and in particular may includetablets and pills, either in a form for intact swallowing (e.g.film-coated) or in a form capable of rapid disintegration (either in theoral cavity after ingestion or in a small amount of liquid prior toingestion), including a chewable form, dry powders, granules, capsulesor sachets containing these granules, wafers, lozenges, and the like.The form for intact swallowing may be film-coated, if desired.

Preferred dosage forms include tablets and pills, either in a form forintact swallowing (e.g. film-coated) in or in a chewable form, granulesand capsules or sachets containing these granules, and lozenges.

In the case of orally administrate dosage forms, if desired film-coated,these are swallowed intact and disintegration takes place in thestomach, whereupon the active agent is released for adsorption ofphosphate to reduce its systemic uptake.

The term “film-coated” as used herein relates to a mixture ofpharmaceutically acceptable excipients which is typically applied to acompressed tablet, beads, granules, or particles of active ingredientthat are compressed into tablets. Alternatively it may also be combinedwith, mixed with or otherwise added to the active agent. It isunderstood that the coating chosen must be compatible with the activeagent. It is further understood that a person skilled in the art willknow how to manipulate the coating to achieve disintegration in thestomach by choosing the excipients which make up the coating, its type,and/or its thickness.

In a preferred embodiment the film coating is applied to apharmaceutical composition comprising the iron oxy-hydroxide and atleast one excipient in compressed form.

Suitable polymers for film-coating according to the present inventionare soluble at pH of from about 1.2 to about 5, such as for examplehydroxypropylmethylcellulose (HPMC) alone and/or in combination withhydroxypropylcellulose (HPC), carboxymethylcellulose, methylcellulose,ethylcellulose, acrylic resins, and polyvinylpyrrolidone and gelatin orother commercially available film-coating preparations such asDri-Klear® (Crompton & Knowles Corp., Mahwah. N J.) or Opadry®(Colorcon, West Point Pa.).

The preferred film coating of this invention is comprised of acommercial film-coating product designed for aqueous film coatingcontaining the water-soluble, film-forming resin, hydroxypropylmethylcellulose and polyethylene glycol (or other suitable plasticizingagents such as propylene glycol or glycerine) and optionally containingtitanium dioxide (or other colorant or opacifying agent). Such a productis commercially available under the trade name Opadry® White (Colorcon,West Point, Pa.).

A suitable blend for coating may comprise 0 to about 20% w/w titaniumdioxide or colorant, about 5 to about 95% w/w hydroxypropylmethylcellulose, and 0 to about 25% w/w polyethylene glycol. The mostpreferred embodiment comprises 10.5% non water additives, of which 7.5%is Opadry®, in relation to the total weight of the coating.

This blend for coating may further comprise flavoring agents,taste-masking agents and salivating agents as defined hereinabove, insmall amounts such as for example 0.1 to 1.0% (w/w), preferably 0.1 to0.4% based on the weight of the total blend for coating. The preferredflavoring and/or taste-masking agent may be selected from the group ofagents as defined hereinabove. The preferred amount is readilydetermined by balancing the goal of adding an amount sufficient to maskthe core tablet taste and provide a distinct, characteristic andpleasing taste, and the goal of keeping the tablet from being too muchlike a candy product. The desired strength of the flavoring and/ortaste-masking agent may vary depending on the type of tablet and theintended recipients and the identity of the flavouring and/ortaste-masking agent.

The amount of coating deposited on the tablet is typically in the rangeof from about 1.0% to about 6.0% weight gain, preferably from 2.0% to4.0% weight gain, which means the weight gain of the tablet upon coatingrelative to the weight of the uncoated tablet.

In the case of orally administrate, rapidly disintegrating dosage forms,disintegration takes place immediately upon administration allowing toquickly release the active agent or forming small particles containingthe active agent in the oral cavity. Suitable disintegration rates rangefrom 1 second to 3 minutes. A preferred disintegration lime is typicallyless than 30 seconds, measured according to standard EuropeanPharmacopeia testing method.

Thus in one embodiment, the formulation is a tablet made by standardtableting techniques, such as direct compression, and dry granulation,comprising iron oxy-hydroxide, a stabilization agent, an excipient(different from the stabilization agent), including, in particular, oneor more sweeteners, taste-enhancing agents, flavouring agents,superdisintegrants, glidant, antioxidants and the like. Wet processingtechniques must be avoided. This is due to the fact that in case ofusing organic solvents, typically isopropanol, solvent remains in thegranulate after drying which might not be compatible with the productspecification.

In case of using water as a solvent for wet granulation, iron releasefrom the product is increased which should be avoided under anycircumstances for the inventive phosphate adsorber compositions.

Extrusion techniques may cause problems in that, when using highloadings of iron, small hard balls are formed which are not suitable forthe invention since they hardly show any phosphate adsorbing properties.

In dry granulation, powdered components are typically mixed prior tobeing compacted, also called pre-compression, to yield hard slugs whichare then ground and sieved before the addition of other ingredients andfinal compression.

Preferably, the compositions of the invention are made by directcompression, which may be considered to be the simplest and the mosteconomical process for producing tablets.

In a preferred embodiment of the invention the compositions of theinvention are made by mixing most of the ingredients (more than 50%,preferably more than 70%, and more preferably more than 90% up to 100%of the total weight of the Ingredients), for example those of theingredients presented in table 1, in the form of an aqueous suspension(amount of dry substance, for example, 1 to 50% (w/w), preferably 10 to40% (w/w), more preferably 20 to 30% (w/w)), subjecting said suspensionto known spray-drying processes under conventional conditions ofexposure to hot gases such as air or preferably nitrogen to temperaturesof from 135° C. to 200° C. to obtain a flowable powder, which isoptionally subsequently mixed with additional ingredients (e.g. as shownin Table 2) and subsequently directly compressed under a range ofcompression forces such as from 10 to 20 kN to obtain a tablet.

Preferably, the suspension contains 3 to 9% (w/w) of iron, morepreferably 4 to 8% (w/w), most preferably 6% (w/w).

Care has to be taken that the diameter and the height of the spraydrying column are sufficiently large. Further, the temperature has to bechosen in a range that the excipients and other ingredients neither meltnor caramelize. Both of these processed do not lead to a dry powder butto a solid melt, which is unsuitable for the present invention.

Preferably, the flowable powder, before tableting, is first compactedusing dry compacting in order to reduce the amount of fine powder (dust)and to homogenize the particle size. In doing this a hardness of theobtained tablets in the range of 25 to 400 N is achieved. Thecompression force is adjusted in a range that the hardness of thetablets obtained from the compacted mixture is 50 to 100 N for chewabletablets, and 100 to 200 N in case of coated tablets or swallowingtablets. If these ranges are used, the disintegration time of theobtained tablets is within the specification required by Ph. Eur.

It has been found surprisingly that, in particular, due to this methodthe amount of excipients required to obtain tablets with suitableproperties, for example in respect to tablet strength, disintegrationbehaviour etc. can be reduced, whereby pharmaceutical compositions, inparticular, in tablet form can be produced having a high load of ironoxy hydroxide.

It is understood that the exact amounts of ingredients will determinethe size and depth of the tablet. Tablets capable of rapiddisintegration (either in the oral cavity, i.e. chewing tablets, or in asmall amount of liquid prior to ingestion) can have any geometricalshape, such as round, square, triangular, etc. Typically they are roundand have preferably a diameter of 15 to 30 mm, most preferably 20 mm anda height of 2 to 8 mm, preferably 4 to 6 mm. Film coated tablets forintact swallowing are typically in oblong form, for example about 19 mmin length, 10 mm in width and 8 mm in height. These examples are merelyillustrative and by no means limiting. A person skilled in the art willknow to choose the appropriate forms depending on the amount of totalingredients.

Compression should be sufficient to hold the ingredients together duringdose administration, while allowing easy disintegration in the oralcavity. Typically 10 to 20 kN are used.

In another embodiment, the pharmaceutical composition is in form ofgranules suitable for disintegration in the oral cavity or rapiddissolution in small amounts of water. The granules may be prepared byhigh shear granulation or preferably fluidized bed granulation or (dry)mixing processes. As pointed out above, wet techniques using solventsmust be avoided. The granules may be filled in capsules or sachets forstorage and administration to the oral cavity.

In a further embodiment, as an alternative to spry-drying, thepharmaceutical composition can be provided in form of a wafer. The wafermay be formed by compressing a powder, lyophilizing a cake, orevaporating a suspension, emulsion or gel. Alternatively, the mixed drymaterials could be flattened or compressed in a compression machine orbetween rollers to form the powder e.g. into a sheet that may be cut toan appropriate size that can be inserted in the oral cavity. In oneembodiment, the wafer is formed by suspending the active agent, solvent,binding agent or other additives in a solvent such as water. Apredetermined amount of the suspension is placed in wells in a plasticmold and lyophilized in the wells to remove the water and form a wafer.

As mentioned hereinabove, the compositions of the invention areindicated for use in the known indications of essentiallynon-bioabsorbable iron oxy-hydroxide, particularly for the selectiveremoval of inorganic phosphate such as in the treatment ofhyperphosphataemia.

Therefore, in a further aspect the invention provides a composition ofthe invention for use in the treatment of hyperphosphataemia.

In another aspect the invention provides a method for treatinghyperphosphataemia comprising administering a composition of theinvention to a patient in need thereof.

In yet another aspect the invention provides the use of a composition ofthe invention in the preparation of a medicament for the treatment ofhyperphosphataemia.

The utility of the compositions of the invention may be observed instandard clinical tests.

The exact amount of iron oxy-hydroxide and composition to beadministered depends on several factors, for example the severity of theillness, the desired duration of treatment and the like.

The invention is explained in more detail by means of the followingspecific, non-limiting examples.

EXAMPLES

Direct compression was performed using a standard tableting press at acompression force of 10 to 20 kN. Spraydrying processes were performedat a temperature of 135 to 200® C.

Tablet Test Methods

Tablet hardness and disintegration time was determined according tostandard European Pharmacopeia testing methods.

Example 1: Preparation of Stabilized Iron Oxy-Hydroxide Premixture

A stabilized iron oxy-hydroxide premixture was prepared by mixingamounts/ratios of an iron oxy-hydroxide suspension (prepared accordingto EP 0 868 125 B1) with the excipients according to Table 1. Thissuspension was subjected to spray-drying at 135 to 200° C. to obtain apremixture in form of a flowable powder. This premixture was subjectedto direct compression to obtain a tablet, the composition of which isshown in Table 1.

TABLE 1 Ex. 1a Ex. 1b Ex. 1c Ex. 1d Ex. 1e Component mg mg mg mg mgFe—OOH 800 800 800 800  800 Saccharose¹⁾ 800 800 800 800 — Nativestarch²⁾ — 533 400 533 — Pregelatinised 800 267 400 267 — starch³⁾Polyplasdone ® — — — 120 — XL⁴⁾ Dextrin²⁾ — — — — 1600 Water⁵⁾ 8400 8400  8400  8400 8400 Disintegration nd nd nd 35 nd time (seconds)¹⁾stabilizer ²⁾filler/disintegrant³⁾stabilizer/binder/filler/disintegrant ⁴⁾superdisintegrant ⁵⁾water isnot present anymore in the premixture after drying, except a remainingportion of approx. 5% of the dry weight (total of other components)

Example 2 Preparation of Tablets

A dry mixture was prepared by mixing the ingredients according to table2 and subjected to direct compression to obtain a tablet.

TABLE 2 Ex. 2a Ex. 2b Ex. 2c Ex. 2d component mg mg mg mg Premixture(according 2500 2500 2500 2500 to Example 1a-d) (1a) (1b) (1c) (1d)Flavour of choice 15 15 15 15 NHDC 0.025 0.025 0.025 0.025 Aerosil ® 2525 25 25 Mg-stearate 12.5 12.5 12.5 12.5 Explotab ® — 12.5 200 —Polyplasdone ® XL — — — 50

Example 3: Film-Coating of Tablets

Tablets obtained according to Example 2, but with only 50% of theamounts, were compressed into oblong form and subsequently film-coated(weight gain from 2 to 5%) by mixing the ingredients according to thefollowing table:

TABLE 3 component mg Opadry ® II White 83.4 Optaflow ® WA 1.7 Apricotaroma 1.7

Example 4: Granules

The powder obtained according to Example 1e was wet granulated usinghigh shear granulation with isopropanol as granulating liquid by addingthe ingredients according to the following table:

TABLE 4 component mg Premixture (Ex. 1e) 2500 Neosorb ® (Sorbitol) 1060Polyvinylpyrrolidon 200 Xanthan 37.5

Example 5: Preparation of a Final Instantly Dispersable Granulate forFilling Into Sachets or Stickpacks

A dry mixture was prepared by mixing the ingredients according to thefollowing table and subjected to subsequent filling into sachets orstickpacks.

TABLE 5 Component mg Granules (Ex. 4, variants obtained 3797.5 fromdifferent base materials) Aspartam 15 Flavour* 70 citric acid 155*“refreshing flavour” such as cola, verveine, blackberry

Example 6: Preparation of a Final Instantly Dispersable Granulate forFilling Into Sachets or Stickpacks

A dry mixture was prepared by mixing the ingredients according to thefollowing table and subjected to subsequent filling into sachets orstickpacks:

TABLE 6 Component mg Granules (Ex. 4, variants obtained 3797.5 fromdifferent base materials Aspartam 25 Caramel aroma 100 Vanilla aroma 30

Example 7: Preparation of Flowable Powders

9.6 kg FeOOH (corresponding to 6.0 kg Fe) was suspended in watertogether with the amounts of excipients and adjuvants shown in Table 7.100 kg of the suspension was subjected to spray-drying. The iron loadingof the obtained powders is given in Table 8.

TABLE 7 Amount of FeOOH Sucrose PST¹⁾ Dextrin Lycatab ®²⁾ Product [kg][kg] [kg] [kg] [kg] a 9.6 8.9 5.9 3.0 b 9.6 6.9 c 9.6 6.9 d 9.6 2.0 2.02.9 e 9.6 1.7 1.7 1.7 1.7 f 9.6 3.0 2.1 0.9 0.9 g 9.6 3.4 2.3 1.1¹⁾potato starch ²⁾pregelatinised starch, available from Roquette

TABLE 8 FeOOH LOD¹⁾ Total amount Fe (Fe × 1.6) (approx.) of productProduct [% w/w] [% w/w] [% w/w] [kg] a 20-22 33.6 4 28.6 b 34-36 56 417.1 c 34-36 56 4 17.1 d 34-36 56 4 17.1 e 34-36 56 4 17.1 f 34-36 56 417.1 g 34-36 56 4 17.1 ¹⁾Loss on drying, determined by a halogenmoisture analyzer (constant mass; change in mass not more than 1 mg per180 seconds).

Example 8: Tableting of the Obtained Flowable Powders

The product obtained in Examples 7a) to g) were mixed with theingredients shown in Table 9a, and tablets were formed of the obtainedmixtures. The Fe content, Fe release at pH 3 and phosphate adsorption ofthe obtained tablets are given in Table 9b.

The Fe release was measured according to European Pharmacopeia chapter2.9.3 using standard dissolution equipment and parameters as describedin the monograph. The test medium was water, pH 3 was adjusted usinghydrochloric acid. Samples were taken after 2 h and iron contentanalyzed by titration.

Phosphate adsorption was measured as described in WO 2006/000547 bydissolving the obtained tablet in a defined amount of phosphate solutionof a specific concentration, adjusting the pH to 3, reacting for 2 hoursat 37° C., centrifugation, decanting and measuring the phosphate contentvia ionic chromatography or photometric determination.

TABLE 9a Amount Component [% w/w] Flowable powder 7a)-7g) 98-93, withoutcoating 98 to 95% Aroma including taste masking 0.2-1 agent(neohesperidine dihydrochalcone) Lubricant/glidant/flow aid total 0.5-2Compression aid (ProSolv ®) 0.5-2 Optionally coating max. 3

TABLE 9b Fe Flowable release Phosphate powder Fe loading at pH 3absorption product used [% w/w] [% w/w] [mg P/mg Fe] 8a 7a 19.5 1.80.314 8b 7b 34.7 3.4 0.319 8c 7c 36.7 0.5 0.241 8d 7d 35.9 0.4 0.216 8e7e 36.3 0.6 0.229 8f 7f 36.2 0.2 0.219 8g 7g 37.5 0.2 0.170

1. Pharmaceutical composition comprising iron oxy-hydroxide in highloading, in a form suitable for oral administration.
 2. Pharmaceuticalcomposition comprising iron oxy-hydroxide in high loading, in a formsuitable for oral administration as film-coated dosage forms for intactswallowing or as dosage forms capable of disintegration in the oralcavity. 3-21. (canceled)
 22. A method for preparing the compositionaccording to claim 1 in the form of a tablet by direct compression ordry granulation.
 23. A method for preparing the composition according toclaim 1 in the form of a tablet, wherein an aqueous suspension,comprising at least 90% (w/w) of the ingredients based on the totalweight of the final composition, is prepared, which is then subjected tospray-drying to obtain a flowable powder, which is optionally mixed withthe remaining ingredients and subsequently compressed to obtain atablet.
 24. A tablet, as obtainable by the method of claim
 23. 25. Atablet comprising iron oxy-hydroxide in an amount of 40 to 65% (w/w),saccharose in an amount of 5 to 30% (w/w), and starch in an amount of 5to 30% (w/w), expressed in relation to the total weight of the tabletcomposition, excluding the weight of an optionally present tabletcoating.